Neuromyelitis optica (NMO) is a rare but devastating inflammatory disorder of the central nervous system (CNS) that primarily affects the optic nerves and spinal cord. NMO was initially characterized as a subset of multiple sclerosis (MS), but is now considered a distinct disease. Currently, there are no FDA approved therapies for NMO. In fact, many MS therapies, most notably interferon-beta (IFN-?), worsens NMO. The limited therapies for NMO demonstrate that this disease has clear unmet needs in neurology. The goal of this project is to understand the immune pathways that initiate disease activity in NMO. The aims of this proposal will address three connected but distinct issues that will have an impact NMO patients. Aim 1 will determine the immune pathways that are present in patients with MS and NMO. This will be achieved by proteomic analysis of plasma and transcriptomic analysis of CD4+ T-cells and B-cells from patients. Aim 2 will assess the direct interaction between B-cell subsets and T helper cells from NMO and healthy volunteers by utilizing cell culturing techniques. Aim 3 will utilize the animal models we have developed to understand the mechanisms underlying the effects BAFF and APRIL have on T cells, neutrophil and B-cells interactions in neuro- autoimmune disease. The first two aims of this proposal will be a highly translation collaboration between Drs. Axtell, Lessard, Pardo (the director of OMRF's MS Center of Excellence), Anaya (Professor of Medicine at Rosario University, Director of the Autoimmune Diseases Research Center) and the Accelerated Cure Project (ACP). The clinical expertise and large patient population Drs. Pardo, Anaya and the ACP will provide to this project will enable these aims to be accomplished. The third aim utilizes our strength in animal models of neuro-autoimmunity that will give insight into the biological mechanisms behind NMO. The combination of research on human subject and the mechanistic animal experiments outlined in this proposal have the potential to give deep insight into pathological processes that underlie and NMO.